A Chemo-Enzymatic Platform for Furanolide Synthesis and Functional Exploration

Furanolides represent an emerging class of natural products known for their structural diversity and potent bioactivities, including antibiotic, cytotoxic, or algicidal effects. The systematic exploration of their biological activity profiles for the discovery of new hits for drug development thus constitutes a promising endeavor. However, their low natural abundance and the resulting difficulty in obtaining sufficient quantities have limited further in-depth investigations into their biological activity and structure-activity relationships (SARs). Building on our recent discovery of biosynthetic enzymes catalyzing furanolide core-structure assembly, we herein developed a cost-effective, one-pot enzymatic toolbox that enables the fast generation of hundreds of furanolide structural analogs. We systematically evaluated antimicrobial activities and cytotoxicity against the A549 lung cancer cell line for a representative selection of library congeners and explored their SARs. Several derivatives demonstrated significant cytotoxicity, particularly against lung cancer stem cells, offering promising insights into the development of furanolides as potential anticancer agents. Additionally, some analogs displayed promising antibacterial activity against important Gram-positive pathogens such asStaphylococcus aureus.